OBJECTIVE: To investigate the in vivo anti-salmonella activity and the safety of aqueous extract of Euphorbia prostratra (E. prostratra), a plant commonly used in Cameroon by traditional healers. METHODS: A Salmonella typhimurium-infected rat model was used for the study. The physiological, biochemical and histopathological markers of possible side effects of this extract were studied using standard methods. RESULTS: The extract had a significant effect on the number of viable Salmonella typhimurium recovered from faeces, and could stop salmonellosis after 8 and 10 days of treatment for male and female rats, respectively, with non-toxic doses. However, the biochemical and histopathological analyses revealed that at relatively high doses (≥ 73.48 mg/kg for female and ≥ 122.71 mg/kg for male) the extract could induce liver damage, as illustrated by a rise of serum transaminases' levels and significant inflammation of the parenchyma and portal vein. Side effects were also observed on the kidneys, as shown by both serum and urinary creatinine, and urinary proteins. CONCLUSIONS: The overall results indicate that the aqueous extract of E. prostrata has the potential to provide an effective treatment for salmonellosis, including typhoid fever. However, it is necessary to extrapolate these results in large animals, in further studies.